Enfuvirtide (Fuzeon, T-20) is a peptide HIV entry inhibitor currently dosed twice daily by subcutaneous injection. While proven to be efficacious and safe, enfuvirtide is under-utilized due to its frequent dosing, cumbersome administration, and inducement of injection site reactions in most patients. In expressing enfuvirtide as a recombinant XTEN fusion, we expect to improve all of these properties and create a longer-acting and more easily administered drug. Amunix has developed the XTEN technology platform to extend the serum half-lives of protein pharmaceuticals. XTEN is a synthetic, unstructured polypeptide chain that increases the apparent molecular weight of proteins to which it is fused, thereby slowing kidney clearance in a manner analogous to conjugation with polyethylene glycol (PEG). Obvious targets for XTEN are peptide drugs which, due to their small size, tend to be eliminated quickly via kidney filtration. XTEN prolongs exposure such that peptides normally dosed twice daily are projected to be administered monthly as XTEN fusions. Additionally, XTEN, due to its unstructured nature, is known to increase the solubility of and limi the aggregation of fused payloads. Modifying these drug properties simplifies manufacturing and use by enabling liquid, rather than lyophilized, formulation. Here, our goal is to combine XTEN with the validated anti-HIV drug enfuvirtide to produce a superior and more clinically relevant pharmaceutical. PUBLIC HEALTH RELEVANCE: Patients infected with HIV are healthiest when taking combination regimens containing drugs that work in different ways. Even though enfuvirtide, which works in a unique way, can be incorporated in these combination regimens, it has disadvantages that limit its inclusion. Here, we propose to use our XTEN technology to make a better version of enfuvirtide that is easier to use, causes fewer side effects, and is less expensive so that it can be taken by more patients.